The major function of the adrenal gland is to regulate metabolism in the body so that an intermittent intake of food can be regulated to maintain a constant metabolite supply to the cells. This is accomplished by producing steroid hormones which can control the conversion of incoming nutrients, such as aminoacids, glucose and fats into storage depots from which they can thereafter be released or interchanged, allowing a continuous flow of optimum energy and growth factors to the cells.
One category of steroids is known as the adrenal androgens. Dehydroepiandrosterone (DHEA) is the principal representative of this category. The adrenal androgens which have an anabolic action are produced with puberty, reach a peak in early adulthood and then, beyond the age of 50, decline to very low levels.
When the body is subjected to stress, physical or mental, e.g. injury, cold, starvation or threats, real or imagined, the adrenal cortico-trophic hormone (ACTH), which is secreted by the pituitary gland, stimulates the adrenal cortex to produce steroids in increased amounts in order to provide the body with resources necessary for response to the stress, storage or release of glucose when needed, lipid deposition or mobilization in order to maintain the energy equilibrium of the body under conditions where extra energy may be needed and/or starvation of the cells becomes a possibility.
Under normal conditions, ACTH stimulates the adrenals to secrete DHEA as well as cortisol in younger persons. In the aging individual, secretion of cortisol continues but that of DHEA declines, thus leading to a relative hypercortisolism which can result in obesity, diabetes and decrease in immune function.
DHEA is metabolized in the body. A major metabolite is etiocholanolone (5-.beta. -androstan-3-.alpha.-ol-17-one, (hereinafter referred to as .alpha.-ET) and in normal individuals it is excreted in amounts of about 0.5 mg/100 ml. .beta.-etiocholanolone (5-.beta.-androstan-3-.beta.-ol-17-one, hereinafter referred to as .beta.-ET), was reported to be a minor metabolite of DHEA although evidence for its presence was based upon unmeasured spots on chromatograph strips observed during measurements of etiocholanolone excretion. Even when large quantities of .beta.-ET are ingested, most of the recovered excretion product is in the form of .alpha.-ET, with less than 5% of .beta.-ET found. Kappas, et al, The Thermogenic Effect and Metabolite Fate of Etiocholanolone in Man, J. Clin. Endocrin. & Metab., 18, 1043-1055 (1958). It is shown in said related application Ser. No. 683,423, that the administration of .alpha.-ET, .beta.-ET or mixtures thereof reproduced the effects of DHEA in preventing the development of hyperglycemia and diabetes. It was also discovere that the effective therapeutic amounts of these compounds are considerably lower than the dosage of DHEA required for maximum effect in normalizing blood sugar and maintaining islet integrity. It has further been found that these compounds are superior anti-obesity agents compared to DHEA.
Two additional metabolites of DHEA are androsterone and epiandrosterone. Both of these compounds are 5-.alpha. isomers and unlike the etiocholanolones are androgenic and show no anti-obesity or anti-hyperglycemic actions.
It is shown in the aforesaid related application Ser. No. 683,423 that the etiocholanolones are useful in the treatment of diabetes in mutant mice and treatment of adult-onset diabetes in obese individuals. DHEA and etiocholanolones are also known to be useful as an anti-obesity agent in animals and humans. Yen et al, Prevention of Obesity in Avy/a Mice by Dehydroepiandrosterone, Lipids, 12(5), 409 (1977); Kritchevsky et al, Influence of Dehydroepiandrosterone (DHEA) Cholesterol Metabolism in Rats, Pharm. Res. Comm., 15, No. 9 (1983); Abrahamsson et al, Catabolic Effects and the Influence on Hormonal Variables under Treatment with Gynodian-Depot or Dehydroepiandrosterone (DHEA) Oenanthate, Maturitas, 3 (1981) 225-234.
It has now been discovered that the administration of 5-.beta. sapogenin chemical precursors of .alpha.-ET and .beta.-ET are useful in preventing the development of obesity, hyperglycemia and diabetes. If the 5 position is unsaturated, then the body reduces it to a mixture of 5-.alpha. and 5-.beta. and it has about one-half the activity of the 5-.beta. sapogenins. The 5-.alpha. sapogenins are not effective in preventing the development of hyperglycemia and diabetes.
It is accordingly the object of this invention to provide a new method for treating obesity, diabetes-obesity syndrome and enhancing the function or by preventing the destruction of the pancreatic islet beta cells using 5-.beta. sapogenins as anti-obesity, antidiabetic and antihyperglycemic agents. This and other objects of the invention will become apparent to those skilled in this art from the following description.